TRIM11 Negatively Regulates IFNβ Production and Antiviral Activity by Targeting TBK1

Ki-Sun Kwon,Byeongwoon Song,Edward Harhaj,Younglang Lee,Chankyu Park

doi:10.1371/journal.pone.0063255

Abstract

The innate immune response is a host defense mechanism against infection by viruses and bacteria. Type I interferons (IFNα/β) play a crucial role in innate immunity. If not tightly regulated under normal conditions and during immune responses, IFN production can become aberrant, leading to inflammatory and autoimmune diseases. In this study, we identified TRIM11 (tripartite motif containing 11) as a novel negative regulator of IFNβ production. Ectopic expression of TRIM11 decreased IFNβ promoter activity induced by poly (I:C) stimulation or overexpression of RIG-I (retinoic acid-inducible gene-I) signaling cascade components RIG-IN (constitutively active form of RIG-I), MAVS (mitochondrial antiviral signaling protein), or TBK1 (TANK-binding kinase-1). Conversely, TRIM11 knockdown enhanced IFNβ promoter activity induced by these stimuli. Moreover, TRIM11 overexpression inhibited the phosphorylation and dimerization of IRF3 and expression of IFNβ mRNA. By contrast, TRIM11 knockdown increased the IRF3 phosphorylation and IFNβ mRNA expression. We also found that TRIM11 and TBK1, a key kinase that phosphorylates IRF3 in the RIG-I pathway, interacted with each other through CC and CC2 domain, respectively. This interaction was enhanced in the presence of the TBK1 adaptor proteins, NAP1 (NF-κB activating kinase-associated protein-1), SINTBAD (similar to NAP1 TBK1 adaptor) or TANK (TRAF family member-associated NF-κB activator). Consistent with its inhibitory role in RIG-I-mediated IFNβ signaling, TRIM11 overexpression enhanced viral infectivity, whereas TRIM11 knockdown produced the opposite effect. Collectively, our results suggest that TRIM11 inhibits RIG-I-mediated IFNβ production by targeting the TBK1 signaling complex.

Highlights

The innate immune system is the first line of host defense against invading pathogens [1]
TRIM11 is a Negative Regulator of Innate Immunity In order to identify new TRIM members that play a role in innate immunity, we examined the effect of expression of twentyeight TRIM proteins on IFNb expression using an IFNb promoter activity assay
We investigated whether TRIM11 reduced IFNb production induced by poly (I:C), which mimics an RNA virus

Summary

Introduction

The innate immune system is the first line of host defense against invading pathogens [1]. Signaling pathways activated downstream of PRRs lead to activation of transcription factors such as NF-kB, AP-1 (activator protein-1) and interferon regulatory factors (IRFs) that induce the expression of pro-inflammatory cytokines and type-I interferons (IFNs). Several molecules have been shown to positively or negatively regulate IFNb production through effects on TBK1 or other components of the RIG-I pathway. Nrdp (neuregulin receptor degradation protein-1) enhances TBK1 activity by catalyzing Lys63-linked polyubiquitination of TBK1 [12]. TAX1BP1 (tax1-binding protein-1) and zinc finger protein A20 ( known as tumor necrosis factor alpha-induced protein 3) terminate antiviral signaling by disrupting Lys63-linked polyubiquitination of TBK1 and IKKe (inducible IKK) [15]. TRIP (TRAF-interacting protein) negatively regulates the production of IFNb by promoting TBK1 degradation through Lys48-linked polyubiquitination [17]. RNF11 impedes antiviral signaling by inhibiting Lys63-linked polyubiquitination of TBK1 [18]

Methods

Results

Conclusion